Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent antiinflammatory agents. Despite this benefit, steroidal GR ligands are not selective. Side effects associated with chronic dosing are believed to be the result of cross-reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have homologous ligand binding domains.
A ligand which is selective for GR over other IRs could modulate (i.e. repress, agonize, partially agonize, or antagonize) and thus can be used to influence the basic, life-sustaining systems of the body including carbohydrate, protein and lipid metabolism and the functions of the cardiovascular, kidney, central nervous, immune, skeletal muscle, and other organ and tissue systems. In this regard, GR modulators have proven useful in the treatment of inflammation, tissue rejection, auto-immunity, malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, and Little's syndrome.
GR modulators are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis. GR active compounds have also been used as immunostimulants, repressors, and wound healing and tissue repair agents.
GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, and cutaneous T-cell lymphoma.
Selective antagonists of the glucocorticoid receptor have been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIV), cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IL-1 expression, anti-retroviral therapy, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa. Cognitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, and anxiety.
The prior art discloses a variety of triarylmethanes including triphenylmethanes useful as dyes or pigments. We have unexpectedly discovered a series of triphenylmethane compounds which selectively modulate the glucocorticoid receptor in relation to the progesterone receptor, minerocorticoid receptor, androgen receptor, and estrogen receptor-alpha. In addition, we provide a series of novel compounds which are selective for GR. Importantly, it has not been known previously that triphenylmethane compounds of this invention are useful as selective glucocorticoid receptor modulators.
Examples of the prior art include:
Aoyama et al. (European Patent application 85301391.0, published Sep. 04, 1985) discloses triarylmethane compounds which include triphenylmethane compounds that function as pigments during the process of determining the reduced form of nicotinamide adenine dinucleotide (phosphate);
Aoyama et al. (European Patent application 85302562.5, published Oct. 30, 1985) discloses triphenylmethane compounds that function as pigments during the process of determining compounds that contain a mercapto group;
Nieto et al. (Biochemistry International, 1990, Vol. 21, No. 2, 305-311) discloses that phenolphthalein, a dye containing a triphenylmethane structure, or a phenolphthalein derivative interacts with the rat estrogen receptor;
Kinoshita et al. (U.S. Pat. No. 5,112,867, issued May 12, 1992) discloses triphenylmethane compounds that are useful for treating osteoporosis; and
Brugnara et al. (International Patent application 97/34589, published Sep. 25, 1997) discloses triphenylmethane compounds that have utility for inhibiting or treating sickle cell diseases and cell proliferation diseases in mammals.